Substituted Phenylcarbamoyl Alkylamino Arene Compounds and N,N&#39;-BIS-Arylurea Compounds

ABSTRACT

Substituted phenylcarbamoyl alkylamino arenes; substituted phenylthiocarbamyl alkylamino arenes; substituted phenylcarbamoyl alkylamino heteroarenes; substituted phenylthiocarbamyl alkylamino heteroarenes; N-substituted aryl, N′-substituted aryl urea compounds; N-substituted aryl, N′-substituted heteroaryl urea compounds; N-substituted aryl, N′-substituted aryl thiourea compounds and N-substituted aryl, N′-substituted heteroaryl thiourea compounds are provided and may find use as androgen receptor modulators. The compounds may find particular use in treating prostate cancer, including castration-resistant prostate cancer and/or hormone-sensitive prostate cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of Ser. No. 13/685,013, filed Nov. 26,2012 as a continuation of Ser. No. 13/500,817, which was filed Apr. 6,2012 as a national phase of PCT/US2010/051770 filed Oct. 7, 2010, whichclaims priority to Ser. No. 61/249,532 filed Oct. 7, 2009. The contentsof these applications are hereby incorporated herein by reference intheir entireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

BACKGROUND OF THE INVENTION

According to the American Cancer Society, prostate cancer is the mostcommonly diagnosed cancer among men in the United States, other thanskin cancer. The American Cancer Society estimates that approximately186,000 new cases of prostate cancer were diagnosed, and approximately29,000 men died of prostate cancer, in the United States alone during2008. Prostate cancer is thus the second-leading cause of cancer deathin men in the United States, after lung cancer.

Metastatic prostate cancer is cancer that has spread beyond the prostateand surrounding tissues into distant organs and tissues. The majority ofmen who die from prostate cancer die from the consequences of metastaticdisease. According to the National Cancer Institute, the median survivalof patients with prostate cancer that has metastasized to distant organsis usually one to three years, and most such patients will die ofprostate cancer. Metastatic prostate cancer is generally divided intotwo states: the hormone-sensitive state and the castration-resistantstate (also referred to as the hormone-refractory state).

Testosterone and other male sex hormones, known collectively asandrogens, can fuel the growth of prostate cancer cells. Androgens exerttheir effects on prostate cancer cells by binding to and activating theandrogen receptor, which is expressed in prostate cancer cells. Whenthey first metastasize to distant sites, most prostate cancers depend onandrogens for growth. These prostate cancers are known as“hormone-sensitive” cancers. Accordingly, the leading therapiescurrently used for the treatment of metastatic prostate cancer arefocused on diminishing, or antagonizing, the effects of androgens onprostate cancer cells. One approach utilizes so-called “anti-androgens,”which are molecules that block the interaction of androgens with theandrogen receptor. Another approach is to reduce the amount of androgensproduced in the body, primarily in the testes. This can be achievedsurgically by removal of both testicles (orchiectomy) or through use ofdrugs known as luteinizing hormone-releasing hormone, or LHRH, agonistdrugs, which lower the native production of testosterone in thetesticles (sometimes called “chemical castration”).

Most metastatic prostate cancer initially is hormone-sensitive and thusresponds to hormonal therapies. However, according to a study publishedin the Oct. 7, 2004 issue of The New England Journal of Medicine,virtually all hormone-sensitive metastatic prostate cancer undergoeschanges that convert it to the castration-resistant state in a median of18-24 months after initiation of hormonal therapy. One of the importantmechanisms by which prostate cancer cells switch from thehormone-sensitive to the castration-resistant state appears to bethrough overexpression of the androgen receptor. In experimentscomparing gene expression in hormone-sensitive and castration-resistantprostate cancer cells, an increase in androgen receptor expression wasthe only gene change consistently associated with castration-resistantdisease. Jan. 1, 2004 issue of Nature Medicine (Chen C D, Welsbie D S,Tran C, et al., “Molecular determinants of resistance to antiandrogentherapy.” Nat Med 2004; 10(1):33-39). Once in this state, prostatecancers generally continue to grow in an androgen-dependent mannerdespite the reduction of testosterone production to very low (i.e.,post-castration) levels. Prostate cancer in this state is known as“castration-resistant” prostate cancer, or CRPC. The switch from thehormone-sensitive to the castration-resistant state following initiationof hormonal therapy is generally determined based on either risinglevels of prostate-specific antigen, or PSA, or documented diseaseprogression as evidenced by imaging tests or clinical symptoms.Metastatic prostate cancer that has become castration-resistant isextremely aggressive; these patients have a median survival of only 10to 16 months.

A primary reason that CRPC is so deadly is that it is difficult totreat. Because therapies currently used for the treatment of metastaticprostate cancer operate by reducing the ability of androgens to fuel thegrowth of prostate cancer cells, they generally are effective only onprostate cancers that remain hormone-sensitive by depending on androgensfor growth. CRPC no longer responds to hormonal therapies that areeffective in the hormone-sensitive state. To further complicate thesituation, due to biological changes in prostate cancer that has enteredthe castration-resistant state, drugs that initially block the androgenreceptor and inhibit growth of hormone-sensitive prostate cancer mayhave precisely the opposite effect and start to fuel the growth of CRPC.For example, Casodex® (bicalutamide), sold by AstraZeneca PLC, directlyblocks the interaction of androgens with the androgen receptor and isthe largest selling of the anti-androgen therapies. However, in an invitro model of castration-resistant prostate cancer in which prostatecancer cell lines were genetically engineered to overexpress theandrogen receptor (thus converting them from the hormone-sensitive tothe castration-resistant state), Casodex® failed effectively to inhibitthe androgen receptor in these cells, and in some cases it became astimulant of the androgen receptor. These findings, which are consistentwith the published human clinical experience with Casodex® in CRPC,render Casodex® an ineffective therapy for the castration-resistantstate of metastatic prostate cancer.

Compounds that bind the androgen receptor, the same target bound byCasodex® and other marketed drugs for metastatic prostate cancer, havebeen developed for use in the castration-resistant state of metastaticprostate cancer. These compounds bind the androgen receptor in a mannerthat renders them effective in treating cancers that have becomerefractory to currently used drugs. For example, certain compoundsdisclosed in U.S. Patent Application Publication Nos. 2007/0004753,2007/0254933 and 2009/0111864 are novel small-molecule androgen receptorantagonists that inhibit androgen receptor function by blocking nucleartranslocation of the androgen receptor and DNA binding.

However, there remains an interest in and need for new and alternativetherapies for the treatment of prostate cancer. Preferably, newtherapies will be effective in treating the hormone-refractory state ofmetastatic prostate cancer.

BRIEF SUMMARY OF THE INVENTION

Compounds of the formula (I) or salts thereof are provided, as aremethods of using the compounds as androgen receptor modulators.Compounds of formula (I) are of the structure:

where W¹, W², Z, Y¹, Y², T, R¹ and R² are as defined herein.

In another variation, compounds of formula (II) or salts thereof areprovided, as are methods of using the compounds as androgen receptormodulators. Compounds of formula (II) are of the structure:

where W¹, W², Z, Y¹, Y², Y³, T, R¹ and R² are as defined herein.

Variations of formula (I) and (II) are also provided. Compounds offormula (I) and (II) or a variation thereof as detailed herein or apharmaceutically acceptable salt of any of the foregoing may findparticular use in the treatment of prostate cancer, including CRPCand/or hormone-sensitive prostate cancer. Pharmaceutical compositionscomprising a compound of formula (I) and (II) or a variation thereof asdetailed herein or a pharmaceutically acceptable salt of any of theforegoing and a pharmaceutically acceptable carrier are also provided.Compositions of substantially pure compounds are also embraced by theinvention. Methods of administering a compound of formula (I) and (II)or a variation thereof as detailed herein or a pharmaceuticallyacceptable salt of any of the foregoing are also provided, as are kitscomprising a compound of formula (I) and (II) and instructions for usein the treatment of prostate cancer.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

The term “about” as used herein refers to the usual range of variationfor the respective value readily known to the skilled person in thistechnical field. Reference to “about” a value or parameter hereinincludes (and describes) embodiments that are directed to that value orparameter per se.

As used herein, the term “androgen receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toan androgen receptor or reduces or eliminates or increases or enhancesor mimics an activity of an androgen receptor. As such, an “androgenreceptor modulator” encompasses both an androgen receptor antagonist andan androgen receptor agonist. It is possible that an androgen receptormodulator may be an androgen receptor antagonist when utilized in thehormone-sensitive state of prostate cancer and an androgen receptoragonist when utilized in the hormone-refractory state of prostatecancer. In some aspects, the androgen receptor modulator binds to orinhibits binding to a ligand to an androgen receptor. In another aspect,the androgen receptor modulator blocks nuclear translocation of theandrogen receptor. In some aspects, the androgen receptor modulatorinhibits binding of a ligand to the androgen receptor by at least aboutor about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or100% as determined in the assays described herein. In some aspects, theandrogen receptor modulator reduces an activity of an androgen receptorby at least or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95% or 100% as compared to the corresponding activity in the samesubject prior to treatment with the androgen receptor modulator orcompared to the corresponding activity in other subjects not receivingthe androgen receptor modulator or as determined by other suitableassays. In some aspects, the androgen receptor modulator enhances anactivity of an androgen receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or400% or 500% or more as compared to the corresponding activity in thesame subject prior to treatment with the androgen receptor modulator orcompared to the corresponding activity in other subjects not receivingthe androgen receptor modulator or as determined by other suitableassays. In some aspects, the androgen receptor modulator is capable ofbinding to the active site of an androgen receptor (e.g., a binding sitefor a ligand). In some embodiments, the androgen receptor modulator iscapable of binding to an allosteric site of an androgen receptor.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human. The individualmay be a male human who has been diagnosed with or is suspected ofhaving a prostate cancer. The individual may be a human who exhibits oneor more symptoms associated with prostate cancer. The individual may bea human who has a mutated or abnormal gene associated with prostatecancer. The individual may be a human who is genetically or otherwisepredisposed to developing prostate cancer.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results, including clinical results. For purposesof this invention, beneficial or desired clinical results include, butare not limited to, alleviation of a symptom and/or diminishment of theextent of a symptom and/or preventing a worsening of a symptomassociated with prostate cancer in an individual. Preferably, treatmentof a disease or condition in an individual with a compound of theinvention or a pharmaceutically acceptable salt thereof is accompaniedby no or fewer side effects than are associated with currently availabletherapies for prostate cancer and/or improves the quality of life of theindividual. Treatment may include, but is not limited to, any one ormore of: converting an individual from an unfavorable circulating tumorcell count to a favorable circulating tumor cell count, enhancingoverall survival time; enhancing progression-free survival time andreducing tumor size.

As used herein, “delaying” development of prostate cancer means todefer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of CRPC is a method that reduces probability ofdisease development in a given time frame and/or reduces extent of thedisease in a given time frame, when compared to not using the method.Such comparisons are typically based on clinical studies, using astatistically significant number of subjects. Development may also referto disease progression that may be initially undetectable and includesoccurrence, recurrence and onset.

As used herein, an “at risk” individual is an individual who is at riskof developing prostate cancer. An individual “at risk” may or may nothave a detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). These risk factors include, but are notlimited to, age, sex, race, diet, history of previous disease, presenceof precursor disease, genetic (i.e., hereditary) considerations, andenvironmental exposure. For example, individuals at risk for CRPCinclude, e.g., those having metastatic hormone-responsive prostatecancer.

As used herein, the term “effective amount” intends such amount of acompound which in combination with its parameters of efficacy andtoxicity, as well as based on the knowledge of the practicing specialistshould be effective in a given therapeutic form. As is understood in theart, an effective amount may be in one or more doses, i.e., a singledose or multiple doses may be required to achieve the desired treatmentendpoint. An effective amount may be considered in the context ofadministering one or more therapeutic agents, and a single agent may beconsidered to be given in an effective amount if, in conjunction withone or more other agents, a desirable or beneficial result may be or isachieved. Suitable doses of any of the co-administered compounds mayoptionally be lowered due to the combined action (e.g., additive orsynergistic effects) of the compounds.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier.

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine and thelike. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Further examples of pharmaceutically acceptable salts includethose listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977January; 66(1):1-19. Pharmaceutically acceptable salts can be preparedin situ in the manufacturing process, or by separately reacting apurified compound of the invention in its free acid or base form with asuitable organic or inorganic base or acid, respectively, and isolatingthe salt thus formed during subsequent purification. It should beunderstood that a reference to a pharmaceutically acceptable saltincludes the solvent addition forms or crystal forms thereof,particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

“Alkyl” refers to and includes saturated linear, branched, or cyclichydrocarbon structures and combinations thereof. Particular alkyl groupsare those having 1 to 12 carbon atoms (a “C₁-C₁₂ alkyl”). Moreparticular alkyl groups are those having 1 to 8 carbon atoms (a “C₁-C₈alkyl”). When an alkyl group having a specific number of carbons isnamed, all geometric isomers having that number of carbons are intendedto be encompassed and described; thus, for example, “butyl” is meant toinclude n-butyl, sec-butyl, iso-butyl, tert-butyl and cyclobutyl;“propyl” includes n-propyl, iso-propyl and cyclopropyl. This term isexemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset ofalkyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantyl. A cycloalkyl comprising more than one ring maybe fused, spiro or bridged, or combinations thereof. A preferredcycloalkyl has from 3 to 12 annular carbon atoms (a “C₃-C₁₂cycloalkyl”). A more preferred cycloalkyl has from 3 to 7 annular carbonatoms (a “C₃-C₇ cycloalkyl”). Examples of cycloalkyl groups includeadamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyland the like.

“Alkenyl” refers to an unsaturated linear, branched, or cyclichydrocarbon group having at least one site of olefinic unsaturation(i.e., having at least one moiety of the formula C═C) and preferablyhaving from 2 to 10 carbon atoms and more preferably 2 to 8 carbonatoms. Examples of alkenyl groups include but are not limited to—CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethyl group of thelater example can be attached to the cyclohexenyl moiety at anyavailable position on the ring.

“Alkynyl” refers to an unsaturated linear, branched, or cyclichydrocarbon group having at least one site of acetylenic unsaturation(i.e., having at least one moiety of the formula C═C) and preferablyhaving from 2 to 10 carbon atoms and more preferably 3 to 8 carbonatoms.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, substituted orunsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl,substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to an alkenyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, substituted orunsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl,substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkynyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to an alkynyl group having from 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, substituted orunsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl,substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Aryl,” “arene” or “Ar” refers to an unsaturated aromatic carbocyclicgroup having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In one variation, the aryl group containsfrom 6 to 14 annular carbon atoms.

“Heteroaryl,” “heteroarene” or “HetAr” refers to an unsaturated aromaticcarbocyclic group having from 2 to 10 annular carbon atoms and at leastone annular heteroatom, including but not limited to heteroatoms such asnitrogen, oxygen and sulfur. A heteroaryl group may have a single ring(e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl).

“Substituted aryl” or “substituted arene” refers to an aryl group havingfrom 1 to 5 substituents including, but not limited to, groups such asalkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, substituted orunsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy,heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano,halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted heteroaryl” or “substituted heteroarene” refers to aheteroaryl group having from 1 to 5 substituents including, but notlimited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy,carbonylalkoxy, acylamino, substituted or unsubstituted amino,aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Aralkyl” refers to a residue in which an aryl moiety is attached to analkyl residue and wherein the aralkyl group may be attached to theparent structure at either the aryl or the alkyl residue. Preferably, anaralkyl is connected to the parent structure via the alkyl moiety.

“Aralkenyl” refers to a residue in which an aryl moiety is attached toan alkenyl residue and wherein the aralkenyl group may be attached tothe parent structure at either the aryl or the alkenyl residue.Preferably, an aralkenyl is connected to the parent structure via thealkenyl moiety.

“Aralkynyl” refers to a residue in which an aryl moiety is attached toan alkynyl residue and wherein the aralkynyl group may be attached tothe parent structure at either the aryl or the alkynyl residue.Preferably, an aralkynyl is connected to the parent structure via thealkynyl moiety.

“Heteroaralkyl” refers to a residue in which a heteroaryl moiety isattached to an alkyl residue and wherein the heroaralkyl group may beattached to the parent structure at either the heroaryl or the alkylresidue. Preferably, a heteroaralkyl is connected to the parentstructure via the alkyl moiety.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturatedor an unsaturated non-aromatic group having a single ring or multiplecondensed rings, and having from 1 to 10 annular carbon atoms and from 1to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen. Aheterocycle comprising more than one ring may be fused, spiro orbridged, or any combination thereof.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to aheterocycle group which is substituted with from 1 to 3 substituentsincluding, but not limited to, substituents such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl,aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano,halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted aralkyl,aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy andthe like. In one variation, a substituted heterocycle is a heterocyclesubstituted with an additional ring, wherein the additional ring may bearomatic or non-aromatic.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. Similarly, a “haloalkenyl” or“haloalkynyl” indicates an alkenyl or alkynyl moiety respectively inwhich at least one H is replaced with a halo group. An alkyl group inwhich each H is replaced with a halo group is referred to as a“perhaloalkyl.” A preferred perhaloalkyl group is trifluoromethyl(—CF₃).

A “substituted” group similarly refers to a group which is substitutedwith from 1 to 5 substituents including, but not limited to,substituents such as alkoxy, substituted alkoxy, acyl, acyloxy,carbonylalkoxy, acylamino, substituted or unsubstituted amino,aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

Compounds

Compounds are detailed herein, including in the Brief Summary of theInvention and the appended claims. Use of the detailed compounds,including any and all stereoisomers, salts and solvates thereof, arecontemplated in the described methods, e.g., as androgen receptormodulators. Further methods of using the compounds of the invention aredetailed throughout.

The invention embraces compounds of the formula (I) or a salt thereof:

wherein:

W¹ is CN, NO₂ or SO₂R⁴;

W² is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl or halogen;

Z is S, O or NR⁵;

Y¹ and Y² are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl,arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y¹and Y² are taken together with the carbon to which they are attached toform a cycle which can be heterocyclic, substituted heterocyclic,cycloalkyl, substituted cycloalkyl;

T is carbon or nitrogen and can be at any position in the ring;

R¹ is —C₁-C₈ alkyl-NR^(a)R^(b), —O—C₁-C₈ alkyl-NR^(c)R^(d) or—C(O)NR^(e)R^(f),

-   -   where:        -   R^(a) is a C₁-C₁₂ alkyl and R^(b) is H or a C₁-C₁₂ alkyl or            R^(a) and R^(b) are taken together with the N to which they            are attached to form a heterocyclic ring;        -   R^(c) is a C₁-C₁₂ alkyl and R^(d) is H or a C₁-C₁₂ alkyl or            R^(c) and R^(d) are taken together with the N to which they            are attached to form a heterocyclic ring;        -   R^(e) is a C₁-C₁₂ alkyl and R^(f) is H or a C₁-C₁₂ alkyl, or            R^(e) and R^(f) are taken together with the N to which they            are attached to form a heterocyclic ring;

R² is hydrogen, halogen, nitro, alkyl or substituted alkyl;

R⁴ is H, alkyl, substituted alkyl, aryl or substituted aryl; and

R⁵ is H, alkyl, substituted alkyl, aryl or substituted aryl.

In one aspect, the salt is a pharmaceutically acceptable salt.

In one variation, the compound is of the formula (I) where W¹ is CN. Ina further variation, W² is alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl or substituted alkynyl. In anothervariation of formula (I), W² is substituted alkyl, substituted alkenylor substituted alkynyl where the alkyl, alkenyl or alkynyl issubstituted with one or more halogens. W² in one aspect is a haloalkyl,haloalkenyl, haloalkynyl or perhaloalkyl. W² in one aspect is asubstituted alkyl. In another variation of formula (I), W² issubstituted alkyl where the alkyl is substituted with one or morehalogens. In one variation of formula (I), W² is a haloalkyl orperhaloalkyl. In another variation of formula (I), W² is a perhaloalkyl.The perhaloalkyl in one variation is a C₁-C₈ perhaloalkyl, such astrihalomethyl. In one such variation, W² is trifluoromethyl. In aparticular variation of formula (I), W¹ is CN and W² is perhaloalkyl. Inanother particular variation of formula (I), W¹ is CN and W² is CF₃.

In one variation of formula (I), Y¹ and Y² are both a C₁-C₈ alkyl. Inone such variation, Y¹ and Y² are the same C₁-C₈ alkyl, such as whenboth Y¹ and Y² are methyl, ethyl, propyl or butyl. In one variation offormula (I), Y¹ and Y² are both methyl or are taken together with thecarbon to which they are attached to form a C₃-C₅ cycloalkyl. In oneaspect, compounds of formula (I) are provided where Y¹ and Y² are bothmethyl. In another aspect, compounds of formula (I) are provided whereone of Y¹ or Y² is hydrogen and the other of Y¹ or Y² is C₁-C₈ alkyl. Inone such aspect, one of Y¹ or Y² is hydrogen and the other of Y¹ or Y²is methyl, ethyl, propyl or butyl. In one variation, compounds offormula (I) are provided where at least one of Y¹ and Y² is alkyl wherethe alkyl is a cycloalkyl. In another variation, compounds of formula(I) are provided where at least one of Y¹ and Y² is substituted alkylwhere the substituted alkyl is a substituted cycloalkyl. In a particularvariation, compounds of formula (I) are provided where one or both of Y¹and Y² are substituted alkyl, substituted alkenyl or substituted alkynylwhere the alkyl, alkenyl or alkynyl is substituted with one or morehalogens. In one such variation, at least one of Y¹ and Y² is ahaloalkyl, haloalkenyl or haloalkynyl. In another such variation, bothY¹ and Y² are a haloalkyl, haloalkenyl or haloalkynyl. In anotheraspect, compounds of formula (I) are provided where Y¹ and Y² are takentogether with the carbon to which they are attached to form a C₃-C₅cycloalkyl. In one such variation, Y¹ and Y² are taken together with thecarbon to which they are attached to form a cyclopropyl, cyclobutyl orcyclopentyl moiety. In a particular of formula (I), Y¹ and Y² are bothmethyl, W¹ is CN. In another particular variation of formula (I), Y¹ andY² are both methyl and W² is a perhaloalkyl such as CF₃. In stillanother variation of formula (I), Y¹ and Y² are both methyl, W¹ is CNand W² is a perhaloalkyl such as CF₃. In still another variation offormula (I), Y¹ is isopropyl, Y² is H, W¹ is CN and W² is a perhaloalkylsuch as CF₃. In a particular variation of formula (I), Y¹ and Y² aretaken together with the carbon to which they are attached to form acyclopropyl, W¹ is CN. In another particular of formula (I), Y¹ and Y²are taken together with the carbon to which they are attached to form acyclopropyl and W² is a perhaloalkyl such as CF₃. In still anothervariation of formula (I), Y¹ and Y² are taken together with the carbonto which they are attached to form a cyclopropyl, W¹ is CN and W² is aperhaloalkyl such as CF₃.

In one aspect, compounds of formula (I) are provided where Z issubstituted N (e.g., NR⁵), S or O. In one variation of formula (I), Z isO. In a particular variation of formula (I), Z is S or O and Y¹ and Y²are both a C₁-C₈ alkyl. In one such variation, Z is O and Y¹ and Y² arethe same C₁-C₈ alkyl. In another variation of formula (I), Z is S or Oand Y¹ and Y² are both methyl or are taken together with the carbon towhich they are attached to form a C₃-C₅ cycloalkyl. In one variation,compounds of formula (I) are provided where Z is O and the compound isfurther defined by one or more of the following structural features: (i)Y¹ and Y² are both a C₁-C₈ alkyl; (ii) W¹ is CN; (iii) W² isperhaloalkyl. In one such variation, compounds of the formula (I) areprovided where Z is O, Y¹ and Y² are the same C₁-C₈ alkyl, W¹ is CN andW² is CF₃. In one particular such variation, compounds of the formula(I) are provided where Z is O, Y¹ and Y² are each methyl, W¹ is CN andW² is CF₃. In one variation, compounds of formula (I) are provided whereZ is O and the compound is further defined by one or more of thefollowing structural features: (i) Y¹ and Y² are taken together with thecarbon to which they are attached to form a C₃-C₅ cycloalkyl; (ii) W¹ isCN; (iii) W² is perhaloalkyl. In one such variation, compounds of theformula (I) are provided where Z is O, Y¹ and Y² are taken together withthe carbon to which they are attached to form a C₃-C₅ cycloalkyl, W¹ isCN and W² is CF₃. In one particular variation, compounds of the formula(I) are provided where Z is O, Y¹ and Y² are taken together with thecarbon to which they are attached to form a cyclopropyl, W¹ is CN and W²is CF₃.

In one variation of formula (I), T is C. In another variation of formula(I), T is N. It is understood that where applicable, any variation offormula (I) may in one aspect be further defined by T being C. It isunderstood that where applicable, any variation of formula (I) may inone aspect be further defined by T being N. For example, the variationsdescribed herein may in one aspect be further defined by T being C.Additionally, it is understood that the variations described herein mayin another aspect be further defined by T being N.

Compounds of formula (I) are provided where R¹ is —C₁-C₈alkyl-NR^(a)R^(b) where R^(a) is a C₁-C₁₂ alkyl and R^(b) is H or aC₁-C₁₂ alkyl or R^(a) and R^(b) are taken together with the N to whichthey are attached to form a heterocyclic ring. In one aspect, the —C₁-C₈alkyl moiety of —C₁-C₈ alkyl-NR^(a)R^(b) is a —(CH₂)— moiety where n isan integer from 1 to 8. In a particular aspect, n is less than 4. Inanother aspect, n is 1. In one variation, R^(a) is a C₁-C₁₂ alkyl andR^(b) is H. For example, R^(a) in one variation is methyl, ethyl,propyl, butyl or pentyl and R^(b) is H. In a particular variation, R^(a)is a C₁-C₈ alkyl and R^(b) is H. In still another variation, R^(a) is aC₃-C₆ alkyl and R^(b) is H. Compounds of formula (I) are also providedwhere R^(a) is a C₁-C₁₂ alkyl and R^(b) is a C₁-C₁₂ alkyl. In onevariation, R^(a) is a C₃-C₁₂ cycloalkyl and R^(b) is a C₁-C₁₂ alkyl(e.g., methyl). In another variation, R^(a) and R^(b) are independentlya C₁-C₈ alkyl. In one such variation, R^(a) and R^(b) are the sameC₁-C₁₂ alkyl, e.g., when both R^(a) and R^(b) are ethyl. In stillanother variation, R^(a) and R^(b) are independently a C₃-C₆ alkyl. Instill a further variation, compounds of the formula (I) are providedwhere R^(a) and R^(b) are taken together with the N to which they areattached to form a heterocyclic ring. In one aspect, when R^(a) andR^(b) are taken together to form a heterocyclic ring, the ring is a 4-to 7-membered heterocyclic ring. The heterocyclic ring formed by R^(a),R^(b) and the N to which they are attached in one variation containsonly C and N as annular atoms. In one such variation, the heterocyclecontains as annular atoms only C and the N provided when R^(a) and R^(b)are taken together with the N to which they are attached. In aparticular variation of formula (I), R^(a) and R^(b) are taken togetherwith the N to which they are attached to form a pyrrolidinyl orpiperidinyl ring. Where applicable, for any variation of formula (I)detailed herein wherein R¹ is —C₁-C₈ alkyl-NR^(a)R^(b), in a particularaspect, the C₁-C₈ alkyl moiety of —C₁-C₈ alkyl-NR^(a)R^(b) is a—(CH₂)_(n) moiety where n is 1. Thus, R¹ in one variation is—CH₂NR^(a)R^(b) where R^(a) and R^(b) may be as defined herein. In aparticular aspect, R¹ is:

Compounds of the formula (I) where R¹ is as detailed in this paragraphmay be taken together with the variations noted above for W¹, W², Z, Y¹,Y² and T. For example, in one variation the compound is of the formula(I) where R¹ is as detailed in this paragraph and the compound isfurther defined by any one or more of the following structural features:(i) W¹ is CN; (ii) W² is perhaloalkyl (e.g., CF₃); (iii) Z is O; (iv) Y¹and Y² are both methyl and (v) T is C. In another variation the compoundis of the formula (I) where R¹ is as detailed in this paragraph and thecompound is further defined by any one or more of the followingstructural features: (i) W¹ is CN; (ii) W² is perhaloalkyl (e.g., CF₃);(iii) Z is O; (iv) Y¹ and Y² are both methyl, (v) R² is halogen (e.g.,F) and (vi) T is C.

Compounds of formula (I) are provided where R¹ is —O—C₁-C₈alkyl-NR^(c)R^(d) where R^(c) is a C₁-C₁₂ alkyl and R^(d) is H or aC₁-C₁₂ alkyl or R^(c) and R^(d) are taken together with the N to whichthey are attached to form a heterocyclic ring. In one aspect, the —C₁-C₈alkyl moiety of —O—C₁-C₈ alkyl-NR^(c)R^(d) is a —(CH₂)_(n) moiety wheren is an integer from 1 to 8. In a particular aspect, n is less than 4.In another aspect, n is 2. In one variation, R^(c) is a C₁-C₁₂ alkyl andR^(d) is H. For example, R^(c) in one variation is methyl, ethyl,propyl, butyl or pentyl and R^(d) is H. In a particular variation, R^(c)is a C₁-C₈ alkyl and R^(d) is H. In still another variation, R^(c) is aC₁-C₄ alkyl and R^(d) is H. Compounds of formula (I) are also providedwhere R^(c) and R^(d) are independently a C₁-C₁₂ alkyl. In one suchvariation, R^(c) and R^(d) are the same C₁-C₁₂ alkyl, e.g., when bothR^(c) and R^(d) are methyl. In another variation, R^(c) and R^(d) areindependently a C₁-C₈ alkyl. In still another variation, R^(c) and R^(d)are independently a C₁-C₄ alkyl. In still a further variation, compoundsof the formula (I) are provided where R^(c) and R^(d) are taken togetherwith the N to which they are attached to form a heterocyclic ring. Inone aspect, when R^(c) and R^(d) are taken together to form aheterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. Theheterocyclic ring formed by R^(c), R^(d) and the N to which they areattached in one variation contains only C and N as annular atoms. In onesuch variation, the heterocycle contains as annular atoms only C and theN provided when R^(c) and R^(d) are taken together with the N to whichthey are attached. In a particular variation of formula (I), R^(c) andR^(d) are taken together with the N to which they are attached to form apyrrolidinyl or piperidinyl ring. Where applicable, for any variation offormula (I) detailed herein wherein R¹ is —O—C₁-C₈ alkyl-NR^(c)R^(d), ina particular aspect, the C₁-C₈ alkyl moiety of —O—C₁-C₈alkyl-NR^(c)R^(d) is a —(CH₂)_(n) moiety where n is 2. Thus, R¹ in onevariation is —OCH₂CH₂NR^(c)R^(d) where R^(c) and R^(d) may be as definedherein. In a particular aspect, R¹ is:

Compounds of the formula (I) where R¹ is as detailed in this paragraphmay be taken together with the variations noted above for W¹, W², Z, Y¹,Y² and T. For example, in one variation the compound is of the formula(I) where R¹ is as detailed in this paragraph and the compound isfurther defined by any one or more of the following structural features:(i) W¹ is CN; (ii) W² is perhaloalkyl (e.g., CF₃); (iii) Z is O; (iv) Y¹and Y² are both methyl; (v) R² is H, and (vi) T is C.

Compounds of formula (I) are provided where R¹ is —C(O)NR^(e)R^(f) whereR^(e) and R^(f) are as defined in provisions (i) or (ii) or (iii) or(iv): (i) R^(e) and R^(f) are independently H or a C₁-C₁₂ alkyl; (ii)R^(e) is a C₁-C₁₂ alkyl and R^(f) is H or a C₁-C₁₂ alkyl; (iii) R^(e) isa C₁-C₁₂ alkyl and R^(f) is C₁-C₁₂ alkyl; or (iv) R^(e) and R^(f) aretaken together with the N to which they are attached to form aheterocyclic ring. In one variation, the compound is of the formula (I)where R¹ is —C(O)NR^(e)R^(f) and R^(e) and R^(f) are independently H ora C₁-C₁₂ alkyl. In still another variation, the compound is of theformula (I) where R¹ is —C(O)NR^(e)R^(f) and R^(e) is a C₁-C₁₂ alkyl andR^(f) is H or a C₁-C₁₂ alkyl. In another variation, the compound is ofthe formula (I) where R¹ is —C(O)NR^(e)R^(f) and R^(e) is a C₁-C₁₂ alkyland R^(f) is C₁-C₁₂ alkyl. In still another variation, the compound isof the formula (I) where R¹ is —C(O)NR^(e)R^(f) and R^(e) and R^(f) aretaken together with the N to which they are attached to form aheterocyclic ring. In a particular variation, R^(e) is a C₁-C₁₂ alkyland R^(f) is H. For example, R^(e) in one variation is methyl, ethyl,propyl, butyl, pentyl or hexyl and R^(f) is H. In another particularvariation, R^(e) is a C₃-C₁₂ cycloalkyl (e.g., cyclopentyl) and R^(f) isH. In a further variation, R^(e) is a C₃-C₁₂ branched alkyl (e.g.,tert-butyl) and R^(f) is H. In a particular variation, R^(e) is a C₁-C₈alkyl and R^(f) is H (e.g., where R^(e) is methyl and R^(f) is H). Instill another variation, R^(e) is a C₃-C₆ alkyl and R^(f) is H (e.g.,where R^(e) is propyl or butyl and R^(f) is H). In another particularvariation, R^(e) is a C₁-C₁₂ alkyl and R^(f) is a C₁-C₁₂ alkyl (e.g.,where R^(e) is ethyl and R^(f) is methyl). Compounds of formula (I) arealso provided where R^(e) and R^(f) are independently a C₁-C₁₂ alkyl(e.g., where both R^(e) and R^(f) are methyl). In a further variation,compounds of formula (I) are provided where R^(e) and R^(f) areindependently a C₁-C₁₂ alkyl. In one such variation, R^(e) and R^(f) arethe same C₁-C₁₂ alkyl, e.g., when both R^(e) and R^(f) are ethyl. Inanother variation, R^(e) and R^(f) are independently a C₁-C₈ alkyl. Instill another variation, R^(e) and R^(f) are independently a C₃-C₆alkyl. In one such variation, at least one of R^(e) and R^(f) is a C₃-C₆cycloalkyl. In still a further variation, compounds of the formula (I)are provided where R^(e) and R^(f) are taken together with the N towhich they are attached to form a heterocyclic ring. In one aspect, whenR^(e) and R^(f) are taken together to form a heterocyclic ring, the ringis a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed byR^(e), R^(f) and the N to which they are attached in one variationcontains only C and N as annular atoms. In one such variation, theheterocycle contains as annular atoms only C and the N provided whenR^(e) and R^(f) are taken together with the N to which they areattached. In a particular variation of formula (I), R^(e) and R^(f) aretaken together with the N to which they are attached to form apyrrolidinyl or piperidinyl ring. In a particular aspect, R¹ is:

Compounds of the formula (I) where R¹ is as detailed in this paragraphmay be taken together with the variations noted above for W¹, W², Z, Y¹,Y² and T. For example, in one variation the compound is of the formula(I) where R¹ is as detailed in this paragraph and the compound isfurther defined by any one or more of the following structural features:(i) W¹ is CN; (ii) W² is perhaloalkyl (e.g., CF₃); (iii) Z is O; (iv) Y¹and Y² are both methyl and (vi) T is C. In another exemplary variationthe compound is of the formula (I) where R¹ is as detailed in thisparagraph and the compound is further defined by any one or more of thefollowing structural features: (i) W¹ is CN; (ii) W² is perhaloalkyl(e.g., CF₃); (iii) Z is O; (iv) Y¹ and Y² are taken together with thecarbon to which they are attached to form a cyclopropyl and (vi) T is C.

In any variation detailed herein, R² in one variation is halo (e.g., F).In another variation, R² is H. In one variation, R² is halo when R¹ is—C₁-C₈ alkyl-NR^(a)R^(b) or —C(O)NR^(e)R^(f). In a further variation, R²is H when R¹ is —O—C₁-C₈ alkyl-NR^(c)R^(d).

In a certain variation, the compound of formula (I) has the structure offormula (I-A):

where Z, Y¹, Y², T, R¹ and R² are as defined in formula (I) or anyvariation thereof.

In another variation, the compound of formula (I) has the structure offormula (I-B):

where W¹, W², T, R¹ and R² are as defined in formula (I) or anyvariation thereof.

In a further variation, the compound of formula (I) has the structure offormula (I-C):

where T, R¹ and R² are as defined in formula (I) or any variationthereof.

In a further variation, the compound of formula (I) has the structure offormula (I-D):

where R¹ and R² are as defined in formula (I) or any variation thereof.

In a further variation, the compound of formula (I) has the structure offormula (I-E):

where R¹ is as defined in formula (I) or any variation thereof.

In a further variation, the compound of formula (I) has the structure offormula (I-F):

where n is an integer from 1 to 8 and R^(a) and R^(b) are as defined informula (I) or any variation thereof.

In a further variation, the compound of formula (I) has the structure offormula (I-G):

where n is an integer from 1 to 8 and R^(c) and R^(d) are as defined informula (I) or any variation thereof.

In a further variation, the compound of formula (I) has the structure offormula (I-H):

where R^(e) and R^(f) are as defined in formula (I) or any variationthereof.

In a further variation, the compound of formula (I) has the structure offormula (I-J):

where n is 0 to 3, and R^(e) and R^(f) are as defined in formula (I) orany variation thereof.

The invention embraces compounds of the formula (II) or a salt thereof

wherein:

W¹ is CN, NO₂ or SO₂R⁴;

W² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl or halogen;

Z is S, O or NR⁵;

Y¹ and Y² are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl,arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y¹and Y² are taken together with the carbon to which they are attached toform a cycle which can be heterocyclic, substituted heterocyclic,cycloalkyl, substituted cycloalkyl;

Y³ is carboxyl, formyl, alkyl carbonyl, substituted alkyl carbonyl,alkenyl carbonyl, substituted alkenyl carbonyl, alkynyl carbonyl,substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl,heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkylcarbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkylcarbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl,cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl,N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkylaminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl,halocarbonyl, hydroxymethyl, alkylhydroxymethyl, substitutedalkoxymethyl,

thiocarboxyl, thioformyl, alkyl thiocarbonyl, substituted alkylthiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl,alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, arylthiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl,substituted heteroaryl thiocarbonyl, arylalkyl thiocarbonyl, arylalkenylthiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyl thiocarbonyl,heterocyclyl thiocarbonyl, substituted heterocyclyl thiocarbonyl,thiocarbamyl, N-alkyl thiocarbamyl, N,N-dialkyl thiocarbamyl,N-substituted alkyl thiocarbamyl, N,N-bis-substituted alkylthiocarbamyl, alkoxy thiocarbonyl, substituted alkoxy thiocarbonyl,halothiocarbonyl, mercaptomethyl, substituted alkylthiomethyl;

heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkylcarbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkylcarbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl,cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl,N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkylaminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl,halocarbonyl, hydroxymethyl, alkoxymethyl, substituted alkoxymethyl;

T is carbon or nitrogen and can be at any position in the ring;

R¹ is hydrogen, —C₁-C₈ alkyl-NR^(a)R^(b), —O—C₁-C₈ alkyl-NR^(c)R^(d),—C(O)NR^(e)R^(f) or —NR^(g)R^(h),

-   -   where:        -   R^(a) is a C₁-C₁₂ alkyl and R^(h) is H or a C₁-C₁₂ alkyl or            R^(a) and R^(h) are taken together with the N to which they            are attached to form a heterocyclic ring;        -   R^(c) is a C₁-C₁₂ alkyl and R^(d) is H or a C₁-C₁₂ alkyl or            R^(c) and R^(d) are taken together with the N to which they            are attached to form a heterocyclic ring;        -   R^(e) is H or a C₁-C₁₂ alkyl and R^(f) is H or a C₁-C₁₂            alkyl, or R^(e) and R^(f) are taken together with the N to            which they are attached to form a heterocyclic ring;        -   R^(g) is H or a C₁-C₁₂ alkyl and R^(h) is H or a C₁-C₁₂            alkyl, or R^(g) and R^(h) are taken together with the N to            which they are attached to form a heterocyclic ring;

R² is hydrogen, halogen, nitro, alkyl or substituted alkyl;

R⁴ is H, alkyl, substituted alkyl, aryl or substituted aryl;

R⁵ is H, alkyl, substituted alkyl, aryl or substituted aryl.

In one variation, the compound is of the formula (II) where T isnitrogen when R⁴ and R⁵ are both hydrogen.

In one variation, the compound is of the formula (II) where W¹ is CN. Ina further variation, W² is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl or substituted alkynyl. In anothervariation of formula (II), W² is substituted alkyl, substituted alkenylor substituted alkynyl where the alkyl, alkenyl or alkynyl issubstituted with one or more halogens. W² in one aspect is a haloalkyl,haloalkenyl, haloalkynyl or perhaloalkyl. W² in one aspect is asubstituted alkyl. In another variation of formula (II), W² issubstituted alkyl where the alkyl is substituted with one or morehalogens. In one variation of formula (II), W² is a haloalkyl orperhaloalkyl. In another variation of formula (II), W² is aperhaloalkyl. The perhaloalkyl in one variation is a C₁-C₈ perhaloalkyl,such as trihalomethyl. In one such variation, W² is trifluoromethyl. Ina particular variation of formula (II), W¹ is CN and W² is perhaloalkyl.In another particular variation of formula (II), W¹ is CN and W² is CF₃.In another variation of formula (II), W² is hydrogen. In a particularvariation of formula (II), W¹ is CN and W² is hydrogen.

In one variation of formula (II), Y¹ and Y² are both a C₁-C₈ alkyl. Inone such variation, Y¹ and Y² are the same C₁-C₈ alkyl, such as whenboth Y¹ and Y² are methyl, ethyl, propyl or butyl. In one variation offormula (II), Y¹ and Y² are both methyl or are taken together with thecarbon to which they are attached to form a C₃-C₅ cycloalkyl. In oneaspect, compounds of formula (II) are provided where Y¹ and Y² are bothmethyl. In another aspect, compounds of formula (II) are provided whereone of Y¹ or Y² is hydrogen and the other of Y¹ or Y² is C₁-C₈ alkyl. Inone such aspect, one of Y¹ or Y² is hydrogen and the other of Y¹ or Y²is methyl, ethyl, propyl or butyl. In one variation, compounds offormula (II) are provided where at least one of Y¹ and Y² is alkyl wherethe alkyl is a cycloalkyl. In another variation, compounds of formula(II) are provided where at least one of Y¹ and Y² is substituted alkylwhere the substituted alkyl is a substituted cycloalkyl. In a particularvariation, compounds of formula (II) are provided where one or both ofY¹ and Y² are substituted alkyl, substituted alkenyl or substitutedalkynyl where the alkyl, alkenyl or alkynyl is substituted with one ormore halogens. In one such variation, at least one of Y¹ and Y² is ahaloalkyl, haloalkenyl or haloalkynyl. In another such variation, bothY¹ and Y² are a haloalkyl, haloalkenyl or haloalkynyl. In anotheraspect, compounds of formula (II) are provided where Y¹ and Y² are takentogether with the carbon to which they are attached to form a C₃-C₅cycloalkyl. In one such variation, Y¹ and Y² are taken together with thecarbon to which they are attached to form a cyclopropyl, cyclobutyl orcyclopentyl moiety. In a particular variation of formula (II), Y¹ and Y²are both methyl, W¹ is CN. In another particular variation of formula(II), Y¹ and Y² are both methyl and W² is a perhaloalkyl such as CF₃. Instill another variation of formula (II), Y¹ and Y² are both methyl, W¹is CN and W² is a perhaloalkyl such as CF₃. In still another variationof formula (II), Y¹ is isopropyl, Y² is H, W¹ is CN and W² is aperhaloalkyl such as CF₃. In a particular variation of formula (II), Y¹and Y² are taken together with the carbon to which they are attached toform a cyclopropyl, W¹ is CN. In another particular of formula (II), Y¹and Y² are taken together with the carbon to which they are attached toform a cyclopropyl and W² is a perhaloalkyl such as CF₃. In stillanother variation of formula (II), Y¹ and Y² are taken together with thecarbon to which they are attached to form a cyclopropyl, W¹ is CN and W²is a perhaloalkyl such as CF₃.

In a variation of formula (II), Y³ is carboxyl, carbonyl or derivativethereof, such as carboxyl, formyl, alkyl carbonyl, substituted alkylcarbonyl, alkenyl carbonyl, substituted alkenyl carbonyl, alkynylcarbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted arylcarbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl,arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl,heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclylcarbonyl, cyano, carbamyl, N-alkyl carbamyl, N,N-dialkyl carbamyl,N-substituted alkyl carbamyl, N,N-bis-substituted alkyl carbamyl, alkoxycarbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl,alkylhydroxymethyl or substituted alkoxymethyl. In a variation offormula (II), Y³ is thiocarboxyl, thioformyl, alkyl thiocarbonyl,substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substitutedalkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynylthiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl,heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkylthiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl,heteroaralkyl thiocarbonyl, heterocyclyl thiocarbonyl, substitutedheterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl,N,N-dialkyl thiocarbamyl, N-substituted alkyl thiocarbamyl,N,N-bis-substituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substitutedalkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substitutedalkylthiomethyl.

In a particular variation of formula (II), Y³ is thiocarboxyl orcarboxyl. In a particular variation of formula (II), Y³ is carboxyl.

In a particular variation of formula (II), Y³ is aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkyl aminocarbonyl. In a particular variation offormula (II), Y³ is aminocarbonyl.

In another particular variation of formula (II), Y³ is formyl, alkylcarbonyl or alkoxy carbonyl. In a particular variation of formula (II),Y³ is alkoxycarbonyl.

In a variation of formula (II), Y³ is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substitutedheterocyclyl,

In one aspect, compounds of formula (II) are provided where Z issubstituted N (e.g., NR⁵), S or O. In one variation of formula (II), Zis O. In one variation of formula (II), Z is S. In a particularvariation of formula (II), Z is S or O and Y¹ and Y² are both a C₁-C₈alkyl. In one such variation, Z is S or O and Y¹ and Y² are the sameC₁-C₈ alkyl. In another variation of formula (II), Z is S or O and Y¹and Y² are both methyl or are taken together with the carbon to whichthey are attached to form a C₃-C₅ cycloalkyl.

In one variation, compounds of formula (II) are provided where Z is Sand the compound is further defined by one or more of the followingstructural features: (i) Y¹ and Y² are both a C₁-C₈ alkyl; (ii) W¹ isCN; (iii) W² is perhaloalkyl. In one such variation, compounds of theformula (II) are provided where Z is S, Y¹ and Y² are the same C₁-C₈alkyl, W¹ is CN and W² is CF₃. In one particular such variation,compounds of the formula (II) are provided where Z is S, Y¹ and Y² areeach methyl, W¹ is CN and W² is CF₃. In one particular such variation,compounds of the formula (II) are provided where Z is S, Y¹ and Y² areeach methyl, Y³ is carboxyl, W¹ is CN and W² is CF₃. In one variation,compounds of formula (II) are provided where Z is S and the compound isfurther defined by one or more of the following structural features: (i)Y¹ and Y² are taken together with the carbon to which they are attachedto form a C₃-C₅ cycloalkyl; (ii) W¹ is CN; (iii) W² is perhaloalkyl,(iv) Y³ is carboxyl. In one such variation, compounds of the formula(II) are provided where Z is S, Y¹ and Y² are taken together with thecarbon to which they are attached to form a C₃-C₅ cycloalkyl, W¹ is CNand W² is CF₃. In one particular variation, compounds of the formula(II) are provided where Z is O, Y¹ and Y² are taken together with thecarbon to which they are attached to form a cyclopropyl, Y³ is carboxyl,W¹ is CN and W² is CF₃.

In one variation, compounds of formula (II) are provided where Z is Sand the compound is further defined by one or more of the followingstructural features: (i) Y¹ and Y² are both a C₁-C₈ alkyl; (ii) W¹ isCN; (iii) W² is perhaloalkyl; (iv) Y³ is selected from the groupconsisting of thiocarboxyl, aminocarbonyl, N-alkyl aminocarbonyl,N,N-dialkyl aminocarbonyl, formyl, alkyl carbonyl or alkoxycarbonyl. Inone particular such variation Y³ is alkoxycarbonyl or aminocarbonyl. Inone particular such variation, compounds of the formula (II) areprovided where Z is S, Y¹ and Y² are each methyl, Y³ is alkoxycarbonylor aminocarbonyl, W¹ is CN and W² is CF₃. In one variation, compounds offormula (II) are provided where Z is S and the compound is furtherdefined by one or more of the following structural features: (i) Y¹ andY² are taken together with the carbon to which they are attached to forma C₃-C₅ cycloalkyl; (ii) W¹ is CN; (iii) W² is perhaloalkyl, (iv) Y³ isalkoxycarbonyl or aminocarbonyl. In one such variation, compounds of theformula (II) are provided where Z is S, Y¹ and Y² are taken togetherwith the carbon to which they are attached to form a C₃-C₅ cycloalkyl,W¹ is CN and W² is CF₃. In one particular variation, compounds of theformula (II) are provided where Z is O, Y¹ and Y² are taken togetherwith the carbon to which they are attached to form a cyclopropyl, Y³ isalkoxycarbonyl or aminocarbonyl, W¹ is CN and W² is CF₃.

In one variation of formula (II), T is C. In another variation offormula (II), T is N. It is understood that where applicable, anyvariation of formula (II) may in one aspect be further defined by Tbeing C. It is understood that where applicable, any variation offormula (II) may in one aspect be further defined by T being N. Forexample, the variations described herein may in one aspect be furtherdefined by T being C. Additionally, it is understood that the variationsdescribed herein may in another aspect be further defined by T being N.

Compounds of formula (II) are provided where R¹ is —C₁-C₈alkyl-NR^(a)R^(b) where R^(a) is a C₁-C₁₂ alkyl and R^(b) is H or aC₁-C₁₂ alkyl or R^(a) and R^(b) are taken together with the N to whichthey are attached to form a heterocyclic ring. In one aspect, the —C₁-C₈alkyl moiety of —C₁-C₈ alkyl-NR^(a)R^(b) is a —(CH₂)_(n) moiety where nis an integer from 1 to 8. In a particular aspect, n is less than 4. Inanother aspect, n is 1. In one variation, R^(a) is a C₁-C₁₂ alkyl andR^(b) is H. For example, R^(a) in one variation is methyl, ethyl,propyl, butyl or pentyl and R^(b) is H. In a particular variation, R^(a)is a C₁-C₈ alkyl and R^(b) is H. In still another variation, R^(a) is aC₃-C₆ alkyl and R^(b) is H. Compounds of formula (II) are also providedwhere R^(a) is a C₁-C₁₂ alkyl and R^(b) is a C₁-C₁₂ alkyl. In onevariation, R^(a) is a C₃-C₁₂ cycloalkyl and R^(b) is a C₁-C₁₂ alkyl(e.g., methyl). In another variation, R^(a) and R^(b) are independentlya C₁-C₈ alkyl. In one such variation, R^(a) and R^(b) are the sameC₁-C₁₂ alkyl, e.g., when both R^(a) and R^(b) are ethyl. In stillanother variation, R^(a) and R^(b) are independently a C₃-C₆ alkyl. Instill a further variation, compounds of the formula (II) are providedwhere R^(a) and R^(b) are taken together with the N to which they areattached to form a heterocyclic ring. In one aspect, when R^(a) andR^(b) are taken together to form a heterocyclic ring, the ring is a 4-to 7-membered heterocyclic ring. The heterocyclic ring formed by R^(a),R^(b) and the N to which they are attached in one variation containsonly C and N as annular atoms. In one such variation, the heterocyclecontains as annular atoms only C and the N provided when R^(a) and R^(b)are taken together with the N to which they are attached. In aparticular variation of formula (II), R^(a) and R^(b) are taken togetherwith the N to which they are attached to form a pyrrolidinyl orpiperidinyl ring. Where applicable, for any variation of formula (II)detailed herein wherein R¹ is —C₁-C₈ alkyl-NR^(a)R^(b), in a particularaspect, the C₁-C₈ alkyl moiety of —C₁-C₈ alkyl-NR^(a)R^(b) is a—(CH₂)_(n) moiety where n is 1. Thus, R¹ in one variation is—CH₂NR^(a)R^(b) where R^(a) and R^(b) may be as defined herein. In aparticular aspect, R¹ is:

Compounds of the formula (II) where R¹ is as detailed in this paragraphmay be taken together with the variations noted above for W¹, W², Z, Y¹,Y² and T. For example, in one variation the compound is of the formula(II) where R¹ is as detailed in this paragraph and the compound isfurther defined by any one or more of the following structural features:(i) W¹ is CN; (ii) W² is perhaloalkyl (e.g., CF₃); (iii) Z is S; (iv) Y¹and Y² are both methyl and (v) T is C. In another variation the compoundis of the formula (II) where R¹ is as detailed in this paragraph and thecompound is further defined by any one or more of the followingstructural features: (i) W¹ is CN; (ii) W² is perhaloalkyl (e.g., CF₃);(iii) Z is S; (iv) Y¹ and Y² are both methyl, (v) R² is halogen (e.g.,F) and (vi) T is C.

Compounds of formula (II) are provided where R¹ is —O—C₁-C₈alkyl-NR^(c)R^(d) where R^(c) is a C₁-C₁₂ alkyl and R^(d) is H or aC₁-C₁₂ alkyl or R^(c) and R^(d) are taken together with the N to whichthey are attached to form a heterocyclic ring. In one aspect, the —C₁-C₈alkyl moiety of —O—C₁-C₈ alkyl-NR^(c)R^(d) is a —(CH₂)— moiety where nis an integer from 1 to 8. In a particular aspect, n is less than 4. Inanother aspect, n is 2. In one variation, R^(c) is a C₁-C₁₂ alkyl andR^(d) is H. For example, R^(c) in one variation is methyl, ethyl,propyl, butyl or pentyl and R^(d) is H. In a particular variation, R^(c)is a C₁-C₈ alkyl and R^(d) is H. In still another variation, R^(c) is aC₁-C₄ alkyl and R^(d) is H. Compounds of formula (II) are also providedwhere R^(c) and R^(d) are independently a C₁-C₁₂ alkyl. In one suchvariation, R^(c) and R^(d) are the same C₁-C₁₂ alkyl, e.g., when bothR^(c) and R^(d) are methyl. In another variation, R^(c) and R^(d) areindependently a C₁-C₈ alkyl. In still another variation, R^(c) and R^(d)are independently a C₁-C₄ alkyl. In still a further variation, compoundsof the formula (II) are provided where R^(c) and R^(d) are takentogether with the N to which they are attached to form a heterocyclicring. In one aspect, when R^(c) and R^(d) are taken together to form aheterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. Theheterocyclic ring formed by R^(c), R^(d) and the N to which they areattached in one variation contains only C and N as annular atoms. In onesuch variation, the heterocycle contains as annular atoms only C and theN provided when R^(c) and R^(d) are taken together with the N to whichthey are attached. In a particular variation of formula (II), R^(c) andR^(d) are taken together with the N to which they are attached to form apyrrolidinyl or piperidinyl ring. Where applicable, for any variation offormula (II) detailed herein wherein R¹ is —O—C₁-C₈ alkyl-NR^(c)R^(d),in a particular aspect, the C₁-C₈ alkyl moiety of —O—C₁-C₈alkyl-NR^(c)R^(d) is a —(CH₂)_(n) moiety where n is 2. Thus, R¹ in onevariation is —OCH₂CH₂NR^(c)R^(d) where R^(c) and R^(d) may be as definedherein. In a particular aspect, R¹ is:

Compounds of the formula (II) where R¹ is as detailed in this paragraphmay be taken together with the variations noted above for W¹, W², Z, Y¹,Y² and T. For example, in one variation the compound is of the formula(II) where R¹ is as detailed in this paragraph and the compound isfurther defined by any one or more of the following structural features:(i) W¹ is CN; (ii) W² is perhaloalkyl (e.g., CF₃); (iii) Z is S; (iv) Y¹and Y² are both methyl; (v) R² is H, and (vi) T is C.

Compounds of formula (II) are provided where R¹ is —C(O)NR^(e)R^(f)where R^(e) and R^(f) are as defined in provisions (i) or (ii) or (iii)or (iv): (i) R^(e) and R^(f) are independently H or a C₁-C₁₂ alkyl; (ii)R^(e) is a C₁-C₁₂ alkyl and R^(f) is H or a C₁-C₁₂ alkyl; (iii) R^(e) isa C₁-C₁₂ alkyl and R^(f) is C₁-C₁₂ alkyl; or (iv) R^(e) and R^(f) aretaken together with the N to which they are attached to form aheterocyclic ring. In one variation, the compound is of the formula (II)where R¹ is —C(O)NR^(e)R^(f) and R^(e) and R^(f) are independently H ora C₁-C₁₂ alkyl. In still another variation, the compound is of theformula (II) where R¹ is —C(O)NR^(e)R^(f) and R^(e) is a C₁-C₁₂ alkyland R^(f) is H or a C₁-C₁₂ alkyl. In another variation, the compound isof the formula (II) where R¹ is —C(O)NR^(e)R^(f) and R^(e) is a C₁-C₁₂alkyl and R^(f) is C₁-C₁₂ alkyl. In still another variation, thecompound is of the formula (II) where R¹ is —C(O)NR^(e)R^(f) and R^(e)and R^(f) are taken together with the N to which they are attached toform a heterocyclic ring. In a particular variation, R^(e) is a C₁-C₁₂alkyl and R^(f) is H. For example, R^(e) in one variation is methyl,ethyl, propyl, butyl, pentyl or hexyl and R^(f) is H. In anotherparticular variation, R^(e) is a C₃-C₁₂ cycloalkyl (e.g., cyclopentyl)and R^(f) is H. In a further variation, R^(e) is a C₃-C₁₂ branched alkyl(e.g., ten-butyl) and R^(f) is H. In a particular variation, R^(e) is aC₁-C₈ alkyl and R^(f) is H (e.g., where R^(e) is methyl and R^(f) is H).In still another variation, R^(e) is a C₃-C₆ alkyl and R^(f) is H (e.g.,where R^(e) is propyl or butyl and R^(f) is H). In another particularvariation, R^(e) is a C₁-C₁₂ alkyl and R^(f) is a C₁-C₁₂ alkyl (e.g.,where R^(e) is ethyl and R^(f) is methyl). Compounds of formula (II) arealso provided where R^(e) and R^(f) are independently a C₁-C₁₂ alkyl(e.g., where both R^(e) and R^(f) are methyl). In a further variation,compounds of formula (II) are provided where R^(e) and R^(f) areindependently a C₁-C₁₂ alkyl. In one such variation, R^(e) and R^(f) arethe same C₁-C₁₂ alkyl, e.g., when both R^(e) and R^(f) are ethyl. Inanother variation, R^(e) and R^(f) are independently a C₁-C₈ alkyl. Instill another variation, R^(e) and R^(f) are independently a C₃-C₆alkyl. In one such variation, at least one of R^(e) and R^(f) is a C₃-C₆cycloalkyl. In still a further variation, compounds of the formula (II)are provided where R^(e) and R^(f) are taken together with the N towhich they are attached to form a heterocyclic ring. In one aspect, whenR^(e) and R^(f) are taken together to form a heterocyclic ring, the ringis a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed byR^(e), R^(f) and the N to which they are attached in one variationcontains only C and N as annular atoms. In one such variation, theheterocycle contains as annular atoms only C and the N provided whenR^(e) and R^(f) are taken together with the N to which they areattached. In a particular variation of formula (II), R^(e) and R^(f) aretaken together with the N to which they are attached to form apyrrolidinyl or piperidinyl ring. In a particular aspect, R¹ is:

Compounds of the formula (II) where R¹ is as detailed in this paragraphmay be taken together with the variations noted above for W¹, W², Z, Y¹,Y² and T. For example, in one variation the compound is of the formula(II) where R¹ is as detailed in this paragraph and the compound isfurther defined by any one or more of the following structural features:(i) W¹ is CN; (ii) W² is perhaloalkyl (e.g., CF₃) or hydrogen; (iii) Zis S; (iv) Y¹ and Y² are both methyl and (vi) T is C. In anotherexemplary variation the compound is of the formula (II) where R¹ is asdetailed in this paragraph and the compound is further defined by anyone or more of the following structural features: (i) W¹ is CN; (ii) W²is perhaloalkyl (e.g., CF₃) or hydrogen; (iii) Z is S; (iv) Y¹ and Y²are taken together with the carbon to which they are attached to form acyclopropyl and (vi) T is C.

In any variation detailed herein, R² in one variation is halo (e.g., F).In another variation, R² is H. In one variation, R² is halo when R¹ is—C₁-C₈ alkyl-NR^(a)R^(b) or —C(O)NR^(e)R^(f). In a further variation, R²is H when R¹ is —O—C₁-C₈ alkyl-NR^(c)R^(d).

In any variation detailed herein, Y³ is thiocarboxyl, carboxyl,aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, formyl,alkyl carbonyl or alkoxy carbonyl. In a particular variation of formula(II), Y³ is carboxyl. In another particular variation of formula (II),Y³ is alkoxycarbonyl. In another particular variation of formula (II),Y³ is aminocarbonyl.

In a certain variation, the compound of formula (II) has the structureof formula (II-A):

where Y¹, Y², Y³, T, R¹ and R² are as defined in formula (II) or anyvariation thereof.

In another variation, the compound of formula (II) has the structure offormula (II-B):

where W¹, W², Y³, T, R¹ and R² are as defined in formula (II) or anyvariation thereof.

In a further variation, the compound of formula (II) has the structureof formula (II-C):

where Y³, T, R¹ and R² are as defined in formula (II) or any variationthereof.

In a further variation, the compound of formula (II) has the structureof formula (II-D):

where Y³, R¹ and R² are as defined in formula (II) or any variationthereof.

In a further variation, the compound of formula (II) has the structureof formula (II-E):

where Y³ and R¹ is as defined in formula (I) or any variation thereof.

In a further variation, the compound of formula (II) has the structureof formula (II-F):

where n is an integer from 1 to 8 and Y³, R^(a) and R^(b) are as definedin formula (II) or any variation thereof.

In a further variation, the compound of formula (II) has the structureof formula (II-G):

where n is an integer from 1 to 8 and Y³, R^(c) and R^(d) are as definedin formula (II) or any variation thereof.

In a further variation, the compound of formula (II) has the structureof formula (II-H):

where Y³, R^(e) and R^(f) are as defined in formula (II) or anyvariation thereof.

In a further variation, the compound of formula (II) has the structureof formula (II-J):

where n is 0 to 3, and Y³, R^(e) and R^(f) are as defined in formula(II) or any variation thereof.

In a further variation, the compound of formula (II) has the structureof formula (II-K):

where Y¹, Y², Y³, R¹ and R² are as defined in formula (II) or anyvariation thereof.

In a further variation, the compound of formula (II) has the structureof formula (II-L):

where n is 0 to 3, and Y¹, Y², Y³, R^(e) and R^(f) are as defined informula (II) or any variation thereof.

In a further variation, the compound of formula (II) has the structureof formula (II-M):

where Y¹, Y² and Y³ are as defined in formula (II) or any variationthereof.

In a variation of any one of formula (II-A), (II-B), (II-C), (II-D),(II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II-L) to (II-M)detailed herein, in particular embodiments Y³ is thiocarboxyl, carboxyl,aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, formyl,alkyl carbonyl or alkoxy carbonyl. In a particular variation of any oneof formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G),(II-H), (II-J), (II-K), (II-L) to (II-M) detailed herein, Y³ iscarboxyl. In another particular variation of any one of formula (II-A),(II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-J), (II-K),(II-L) to (II-M) detailed herein, Y³ is alkoxy carbonyl. In anotherparticular variation of any one of formula (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II-L) to (II-M)detailed herein, Y³ is aminocarbonyl.

Examples of compounds according to Formula (I) are depicted in Table 1.The compounds depicted may be present as salts even if salts are notdepicted and it is understood that the invention embraces all salts andsolvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan. It is thus understood that pharmaceutically acceptable salts ofcompounds according the invention are intended.

TABLE 1 Representative Compounds of Formula I. Structure Compound No.

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

Examples of compounds according to Formula (II) are depicted in Table 2.The compounds depicted may be present as salts even if salts are notdepicted and it is understood that the invention embraces all salts andsolvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan. It is thus understood that pharmaceutically acceptable salts ofcompounds according the invention are intended.

TABLE 2 Representative Compounds of Formula II. Structure Compound No.

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. Pharmaceutical compositions accordingto the invention may take a form suitable for oral, buccal, parenteral,nasal, topical or rectal administration, or a form suitable foradministration by inhalation.

Compositions comprising a compound of formula (I), or any variationthereof, or a salt the foregoing are provided, such as compositions ofsubstantially pure compounds. In some embodiments, a compositioncontaining a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E),(I-F), (I-G), (I-H) or (I-J) or a salt of the foregoing is insubstantially pure form. Unless otherwise stated, “substantially pure”intends a composition that contains no more than 35% impurity. Forexample, with reference to a composition of substantially pure compound1 from Table 1, the composition may contain no more than 35% of acompound other than compound 1 or a salt thereof. In one variation, acomposition of substantially pure compound of the formula (I), (I-A),(I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H) or (I-J) or a salt ofthe foregoing is provided wherein the composition contains no more than25% impurity. In another variation, a composition of substantially purecompound of the formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F),(I-G), (I-H) or (I-J) or a salt of the foregoing is provided wherein thecomposition contains or no more than 20% impurity. In still anothervariation, a composition of substantially pure compound of the formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H) or (I-J) ora salt of the foregoing is provided wherein the composition contains orno more than 10% impurity. In a further variation, a composition ofsubstantially pure compound of the formula (I), (I-A), (I-B), (I-C),(I-D), (I-E), (I-F), (I-G), (I-H) or (I-J) or a salt of the foregoing isprovided wherein the composition contains or no more than 5% impurity.In another variation, a composition of substantially pure compound ofthe formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H)or (I-J) or a salt of the foregoing is provided wherein the compositioncontains or no more than 3% impurity. In still another variation, acomposition of substantially pure compound of the formula (I), (I-A),(I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H) or (I-J) or a salt ofthe foregoing is provided wherein the composition contains or no morethan 1% impurity. In a further variation, a composition of substantiallypure compound of the formula (I), (I-A), (I-B), (I-C), (I-D), (I-E),(I-F), (I-G), (I-H) or (I-J) or a salt of the foregoing is providedwherein the composition contains or no more than 0.5% impurity.

Unit dosage forms of a compound of the formula (I), (I-A), (I-B), (I-C),(I-D), (I-E), (I-F), (I-G), (I-H) or (I-J) or a salt of the foregoing isalso provided.

Compositions comprising a compound of formula (II), or any variationthereof, or a salt the foregoing are provided, such as compositions ofsubstantially pure compounds. In some embodiments, a compositioncontaining a compound of formula (II), (II-A), (II-B), (II-C), (II-D),(II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II-L) or (II-M) or asalt of the foregoing is in substantially pure form. Unless otherwisestated, “substantially pure” intends a composition that contains no morethan 35% impurity. For example, with reference to a composition ofsubstantially pure compound 11 from Table 2, the composition may containno more than 35% of a compound other than compound 11 or a salt thereof.In one variation, a composition of substantially pure compound of theformula (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G),(II-H), (II-J), (II-K), (II-L) or (II-M) or a salt of the foregoing isprovided wherein the composition contains no more than 25% impurity. Inanother variation, a composition of substantially pure compound of theformula (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G),(II-H), (II-J), (II-K), (II-L) or (II-M) or a salt of the foregoing isprovided wherein the composition contains or no more than 20% impurity.In still another variation, a composition of substantially pure compoundof the formula (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F),(II-G), (II-H), (II-J), (II-K), (II-L) or (II-M) or a salt of theforegoing is provided wherein the composition contains or no more than10% impurity. In a further variation, a composition of substantiallypure compound of the formula (II), (II-A), (II-B), (II-C), (II-D),(II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II-L) or (II-M) or asalt of the foregoing is provided wherein the composition contains or nomore than 5% impurity. In another variation, a composition ofsubstantially pure compound of the formula (II), (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II-L) or (II-M)or a salt of the foregoing is provided wherein the composition containsor no more than 3% impurity. In still another variation, a compositionof substantially pure compound of the formula (II), (II-A), (II-B),(II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II-L)or (II-M) or a salt of the foregoing is provided wherein the compositioncontains or no more than 1% impurity. In a further variation, acomposition of substantially pure compound of the formula (II), (II-A),(II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-J), (II-K),(II-L) or (II-M) or a salt of the foregoing is provided wherein thecomposition contains or no more than 0.5% impurity.

Unit dosage forms of a compound of the formula (II), (II-A), (II-B),(II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II-L)or (II-M) or a salt of the foregoing is also provided.

Also provided are kits comprising a compound as detailed herein andinstructions for use in the treatment of prostate cancer.

General Description of Biological Assays

The binding properties of compounds disclosed herein to the androgenreceptor may be determined. Binding properties may be assessed bymethods known in the art, such as competitive binding assays. In onevariation, compounds are assessed by the binding assays detailed herein.Compounds disclosed herein may also be tested in cell-based assays or inin vivo models for further characterization. In one aspect, compoundsdisclosed herein are of any formula detailed herein and further inhibitthe binding of a ligand to an androgen receptor. In another aspect,compounds disclosed herein are of any formula detailed herein andfurther exhibit agonist activity to an androgen receptor. In anotheraspect, compounds disclosed herein are of any formula detailed hereinand further exhibit antagonist agonist activity to an androgen receptor.In another aspect, compounds disclosed herein are of any formuladetailed herein and further exhibit efficacy in a preclinical model ofprostate cancer, such as CRPC. In another aspect, compounds disclosedherein are of any formula detailed herein and further exhibit efficacyin a preclinical model of prostate cancer, such as hormone-sensitiveprostate cancer.

In one variation, inhibition of binding of a ligand to a receptor ismeasured in the assays described herein. In another variation,inhibition of binding of a ligand is measured in an assay known in theart. In one variation, binding of a ligand to a receptor is inhibited byat least about 80% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by greater than about any one of 80%,85%, 90%, 95%, 100%, or between about 85-95% or between about 90-100% asdetermined in a suitable assay known in the art such as the assaysdescribed herein. In one variation, binding of a ligand to a receptor isinhibited by at least about 80%±20% as determined in an assay known inthe art.

Overview of the Methods

The compounds described herein may be used to treat, prevent, delay theonset and/or delay the development of prostate cancer in male humans. Amethod of treating metastatic prostate cancer in a human male in needthereof is provided, wherein the method comprises administering to thehuman male an effective amount of a compound of formula (I) or saltthereof or any variation of the foregoing. In one aspect, the compoundsdescribed herein may be used to treat, prevent, delay the onset and/ordelay the development of CRPC. In another aspect, the compoundsdescribed herein may be used to treat, prevent, delay the onset and/ordelay the development of hormone-sensitive prostate cancer.

A method of blocking nuclear translation of an androgen receptor in anindividual in need thereof is provided, comprising administering to theindividual an effective amount of a compound as detailed herein. Amethod of both binding an androgen receptor and preventing its nucleartranslation in an individual in need thereof is provided, comprisingadministering to the individual an effective amount of a compound asdetailed herein. In one aspect, the individual has CRPC. In anotheraspect, the individual has hormone-sensitive prostate cancer.

A method of converting an individual from having unfavorable circulatingtumor cell count to a favorable circulating tumor cell count isprovided, comprising administering to the individual an effective amountof a compound as detailed herein. In one variation, the threshold of 5circulating tumor cells per 7.5 mL of blood is used to stratify patientsinto those with favorable (<5 circulating tumor cells per 7.5 mL) versusunfavorable (>5 circulating tumor cells per 7.5 mL) outcomes asdescribed by Shafer, et al. (“Circulating Tumor Cell Analysis inPatients with Progressive Castration-Resistant Prostate Cancer.” Clin.Cancer Res. (2007), 13(7):2023, Apr. 1, 2007). In one variation, thecirculating tumor cell is associated with CRPC. In one variation, thecirculating tumor cell is associated with hormone-sensitive prostatecancer.

A method of reducing prostate tumor size is provided herein. In onevariation, the tumor size is reduced to at least ⅓ its original size orat least ¼ its original size. In another variation, the tumor size isreduced to about ⅓ its original size or to about ¼ its original size. Inone aspect, the tumor is associated with CRPC. In one aspect, the tumoris associated with hormone-sensitive prostate cancer. Also provided is amethod of increasing apoptosis of prostate cancer cells in an individualin need of such treatment, comprising administering to the individual acompound as detailed here. In some embodiments of the method, theindividual in need of such treatment has CRPC.

In one variation, the method involves administering a compound asdetailed herein to an individual with prostate cancer who has receivedtreatment for prostate cancer with another therapy but who still has oris suspected of having or is susceptible to developing a recurrence ofprostate cancer. Thus, in one aspect, a method of using a compound asdetailed herein as an adjuvant therapy is contemplated, where thecompound is administered to an individual after the individual hasreceived a different first-line or primary therapy. In one method, acompound of formula (I) or salt thereof or any variation of theforegoing is administered to an individual with metastatic prostatecancer as evidenced, e.g., by imaging tests or clinical symptoms. In onemethod, a compound of formula (I) or salt thereof or any variation ofthe foregoing is administered to an individual whose prostate specificantigen levels have increased when comparing their levels at a firsttime to a second time. In one variation, the difference in time betweenthe first time and the second time is at least one month. In anothervariation, the difference in time between the first time and the secondtime is about six months.

A method of using a compound as detailed herein as a first-line therapyagainst prostate cancer in an individual in need thereof is provided,comprising administering to the individual a compound as detailed here.A method of using a compound as detailed herein as a second-line therapyagainst prostate cancer in an individual in need thereof is provided,comprising administering to the individual a compound as detailed here.

It is to be understood that methods described herein also encompassmethods of administering compositions comprising the compounds of theinvention, such as pharmaceutical compositions. Methods of administeringcompositions of substantially pure compounds for use as therapy is alsocontemplated.

Compounds may be administered in an effective dose. In one aspect,compounds may be administered in an amount of up to 240 mg/day.Compounds may be administered by oral, subcutaneous, intravenous orintramuscular routes. Doses of 10 mg/day, 20 mg/day, 40 mg/day, 100mg/day, 200 mg/day, 400 mg/day, 800 mg/day.

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to formula (I) or (II) or a variationthereof unless otherwise indicated.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g. a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

General Method 1

General synthetic method 1 is exemplified in scheme 1. A solution ofappropriate N-aryl-alpha-amino acid (1 equiv) is dissolved in DCM.EDCI-HCl (2 equiv) is added and the reaction mixture stirred for about 5min at RT. An appropriate aryl amine (1.1 equiv) is added portionwiseand stirring is continued for 5 h at RT. Water is added to the reactionmixture, and the product extracted with an appropriate solvent (e.g.DCM). The combined organic layer is washed with water, dried over sodiumsulfate and evaporated under reduced pressure. The crude material ispurified by silica gel chromatography.

General Method 2

General synthetic method 2 is exemplified in scheme 2 and illustratesmethods of making starting materials for use in General Method 1. Takingfor example when Y¹ and Y² are both methyl, to a stirred solution ofappropriate aromatic amine (1 equiv) in 12 mL dry acetone is added1,1,1-trichloro-2-methylpropan-2-ol (2.5-3 equiv). It is understood thatthe reaction may be carried out with other alcohols if Y¹ and Y² areother than methyl. The reaction mixture is cooled to 0° C. Powderedsodium hydroxide is added and the reaction mixture is slowly warmed toRT and stirred at RT for 1 h. The reaction mixture is diluted withdiethyl ether and hexane, and filtered to obtain title compound as thesodium salt.

General Method 3

General synthetic method 3 is exemplified in scheme 3 and illustrates amethod of making starting materials for use in, e.g., General Method 1.The appropriate aryl halide (1 equiv), appropriate alpha-amino acid (1.5equiv), CuI (20 mol %), triethylamine (catalytic amount) and K₂CO₃ (3-4equiv) are dissolved in DMF and water (4:1). The reaction mixture isstirred at RT for 5 min. 2-Acetylcyclohexanone (1.1 equiv) is added andthe reaction mixture is heated at 100° C. for 18 h. The reaction mixtureis acidified with 1 M citric acid (pH 4) and extracted with ethylacetate. The organic layer is dried over Na₂SO₄ and concentrated toobtain the product.

General Method 4

General synthetic method 4 is exemplified in scheme 4 and illustrates amethod of making starting materials for use in, e.g., General Method 5.The appropriate acid (1 equiv) and K₂CO₃ (2 equiv) are dissolved in DMFand water (500:1). The reaction mixture is heated to 40° C. and methyliodide (1.2 equiv) is added. The mixture is heated for 1 h then cooledto RT and added slowly to cooled water (0-10° C.). The resultant slurryis stirred at 0-10° C. for 1-2 h then filtered and the solid dried undervacuum.

General Method 5

General synthetic method 5 is exemplified in scheme 5. The ester fromGeneral Method 4 (1 equiv) and an appropriate aryl isothiocyanate aredissolved in DCM or toluene and the mixture stirred at RT for 1 h. Themixture is then evaporated and the crude product purified bychromatography.

The ester produced in General Method 5 can be converted to the acid oran amide, or reduced to provide an aldehyde or ketone derivative, usingstandard conversion conditions familiar to those skilled in the art.

The methods detailed above may be adapted as known by those of skill inthe art. Particular examples of each General Method are provided in theExamples below.

The following abbreviations are used herein: thin layer chromatography(TLC); Hour (h); Minute (min); Ethanol (EtOH); acetonitrile (ACN);dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroaceticacid (TFA); tetrahydrofuran (THF); Normal(N); aqueous (aq.); methanol(MeOH); dichloromethane (DCM); Retention factor (Rf);1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide Hydrochloride (EDCI-HCl);room temperature (RT).

The following Examples are provided to illustrate but not limit theinvention.

All references disclosed herein are incorporated by reference in theirentirety.

Examples Example 1 Preparation of4-(2-(4-cyano-3-(trifluoromethyl)phenylcarbamoyl)propan-2-ylamino)-2-fluoro-N-methylbenzamide(compound 1)

The title compound was made in accordance with General Method 1.2-(3-Fluoro-4-methylcarbamoyl-phenylamino)-2-methyl-propionic acid (1.27g) was dissolved in DCM. EDCI-HCl (1.91 g) was added to it and thereaction mixture was stirred for 5 min at RT.4-Amino-2-(trifluoromethyl)benzonitrile (1.00 g) was added portionwiseand stirring was continued for 5 h at RT. Water was added to thereaction mixture, and the product was extracted with DCM. The combinedorganic layer was washed with water, dried over sodium sulfate andevaporated under reduced pressure. The residue was purified by silicagel chromatography (100-200 mesh silica gel) eluting with 5% MeOH-DCM toobtain 650 mg of4-[1-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-1-methyl-ethylamino]-2-fluoro-N-methyl-benzamide,HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A:0.05% TFA,Mobile Phase B:ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min,90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 11.174 min,M+1: 423.

Example 2 Preparation of4-(1-(4-cyano-3-(trifluoromethyl)phenylcarbamoyl)cyclopropylamino)-2-fluoro-N-methylbenzamide(compound 2)

A mixture of1-(4-(methylcarbamoyl)-3-fluorophenylamino)cyclopropanecarboxylic acid(200 mg, 0.79 mmol) and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile(270 mg, 1.18 mmol) was heated at 140° C. for 3 h. The crude product waspurified by silica gel chromatography (100-200 mesh silica, 5% acetonein DCM as eluant) to get 40 mg of4-(1-(4-cyano-3-(trifluoromethyl)phenylcarbamoyl)cyclopropylamino)-2-fluoro-N-methylbenzamide,M+1: 421.

Example 3 Preparation of intermediate2-[4-(2-Dimethylamino-ethoxy)-phenylamino]-2-methyl-propionic acid

The title compound may be used to prepare compound 10 in accordance withGeneral Method 1. To a stirred solution of4-(2-dimethylamino-ethoxy)-phenylamine (0.2 g, 1.10 mmol) in dry acetone(12 mL) was added 1,1,1-trichloro-2-methylpropan-2-ol (0.525 g, 2.9mmol). The reaction mixture was cooled to 0° C. Powdered sodiumhydroxide was added and the reaction mixture was slowly warmed to RT andstirred for at RT for 1 h. The reaction mixture was diluted with diethylether and hexane, filtered and washed with hexane to obtain the sodiumsalt of 2-[4-(2-Dimethylamino-ethoxy)-phenylamino]-2-methyl-propionicacid (200 mg).

Example 4 Preparation of intermediate2-(trifluoromethyl)-4-isothiocyanatobenzonitrile

Thiophosgene (10 g, 87.71 mmol) was dissolved in water and stirred at RTfor 10 min. 4-Amino-2-trifluoromethyl-benzonitrile was added portionwiseat RT. The reaction mixture was stirred at RT for 2 h. The product wasextracted with DCM, the organic layer was washed with water and brine,dried over sodium sulphate and evaporated to obtain 12 g of4-isothiocyanato-2-trifluoromethyl-benzonitrile.

Example 5 Preparation of intermediate2-(4-(butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid

The title compound, made in accordance with General Method 3, may beused to prepare compound 4 in accordance with General Method 1.4-Bromo-N-butyl-2-fluorobenzamide (950 mg, 3.22 mmol), 2-aminoisobutyricacid (450 mg, 4.36 mmol), CuI (100 mg, 0.5 mmol), TEA (0.1 mL) and K₂CO₃(1.0 g, 7.2 mmol) were charged in DMF (8 mL) and water (2 mL) andstirred at RT for 5 min. 2-Acetylcyclohexanone (100 mg, 0.7 mmol) wasadded and the reaction mixture was heated at 100° C. for 18 h. Thereaction mixture was acidified with 1 M citric acid (pH 4) and extractedwith ethyl acetate (50 mL, 2 times). The combined organic layer wasdried over Na₂SO₄ and concentrated to obtain 900 mg of2-(4-(butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid.

Example 6 Preparation of2-(4-(tert-butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid

The title compound, made in accordance with General Method 3, may beused to prepare compound 3 in accordance with General Method 1.N-tert-Butyl-4-bromo-2-fluorobenzamide (850 mg, 3.1 mmol),2-aminoisobutyric acid (450 mg, 4.36 mmol), CuI (100 mg, 0.5 mmol), TEA(0.2 mL) and K₂CO₃ (1.0 g, 7.2 mmol) were charged in DMF (8 mL) andwater (2 mL) and stirred at RT for 5 min. 2-Acetylcyclohexanone (100 mg,0.7 mmol) was added and the reaction mixture was heated at 100° C. for18 h. The reaction mixture was acidified with 1 M citric acid (pH 4) andextracted with ethyl acetate (50 mL, 2 times). The combined organiclayer was dried over Na₂SO₄ and concentrated to obtain 1.0 g of2-(4-(tert-butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid.

Example 7 Preparation of2-(4-(propylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid

The title compound, made in accordance with General Method 3, may beused to prepare compound 5 in accordance with General Method 1.4-Bromo-2-fluoro-N-propylbenzamide (620 mg, 2.39 mmol),2-aminoisobutyric acid (422 mg, 4.09 mmol), CuI (100 mg, 0.6 mmol), TEA(catalytic amount) and K₂CO₃ (1.13 g, 8.1 mmol) were dissolved in DMF (8mL) and water (2 mL) stirred at RT for 5 min. 2-Acetylcyclohexanone(0.13 g, 0.3 mmol) was added and the reaction mixture was heated at 100°C. for 18 h. The reaction mixture was acidified with 1 M citric acid (pH4) and extracted with ethyl acetate (100 mL, 2 times). The combinedorganic layer was dried over Na₂SO₄ and concentrated to obtain 1.0 g of2-(4-(propylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid.

Example 8 Preparation ofN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((cyclohexyl(methyl)amino)methyl)-3-fluorophenylamino)-2-methylpropanamide(compound 6)

The title compound is made in accordance with General Method 1, usingthe appropriate substituted 2-phenylamino-2-methylpropanoic acidintermediate that can be made by General Methods 2 or 3.

Example 9 Preparation ofN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((diethylamino)methyl)-3-fluorophenylamino)-2-methylpropanamide(compound 7)

The title compound is made in accordance with General Method 1, usingthe appropriate substituted 2-phenylamino-2-methylpropanoic acidintermediate that can be made by General Methods 2 or 3.

Example 10 Preparation ofN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenylamino)-2-methylpropanamide(compound 8)

The title compound is made in accordance with General Method 1, usingthe appropriate substituted 2-phenylamino-2-methylpropanoic acidintermediate that can be made by General Methods 2 or 3.

Example 11 Preparation ofN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(piperidin-1-ylmethyl)phenylamino)-2-methylpropanamide(compound 9)

The title compound is made in accordance with General Method 1, usingthe appropriate substituted 2-phenylamino-2-methylpropanoic acidintermediate that can be made by General Methods 2 or 3.

Example 12 Preparation of intermediate1-(4-(methylcarbamoyl)-3-fluorophenylamino)cyclopropanecarboxylic acid

To a stirred solution of 4-bromo-2-fluoro-N-methylbenzamide (6.4 g, 27.5mmol), 1-aminocyclopropanecarboxylic acid (4.29 g, 42.4 mmol), CuI(1.047 g, 5.5 mmol), K₂CO₃ (9.50 g, 68.0 mmol), in DMF (64 mL) was addedH₂O (6.4 mL), triethylamine (0.164 mL, 1.1 mmol) followed by 2-acetylcyclohexanone (0.717 g, 5.10 mmol). The reaction mixture was stirred at100° C. overnight. The reaction was monitored by TLC and LCMS. H₂O wasadded, and the aqueous layer was washed with ethyl acetate. The aqueouslayer was acidified with 1M citric acid solution (pH˜4) and extractedwith ethyl acetate. The organic extracts were dried over anhydrousNa₂SO₄, concentrated under reduced pressure and crystallized with DCM toafford 3.01 g of the title compound as an off-white solid.

Example 13 Preparation of intermediate2-(4-(methylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid

4-Bromo-2-fluoro-N-methylbenzamide (155 mg, 0.66 mmol), isoaminobutyricacid (103 mg, 1.0 mmol), CuI (3 mg, 0.015 mmol), triethylamine (0.1 mL,catalytic amount) and K₂CO₃ (353 mg, 2.5 mmol) were dissolved in DMF (4mL) and water (1 mL) stirred at RT for 5 min. 2-Acetylcyclohexanone (100mg, 0.7 mmol) was added and the mixture heated at 100° C. for 18 h. Thereaction mixture was acidified with 1 M citric acid (to pH 4) andextracted with ethyl acetate (50 mL, 2 times). The organic layer wasdried over Na₂SO₄ and concentrated to obtain 200 mg of2-(4-(methylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid.

Example B1 Determination of the Ability of Compounds of the Invention toBind to the Androgen Receptor

The binding assay for evaluating the ability of compounds to interactwith the androgen receptor is a filter binding assay that monitors thedisplacement of a radioactive androgen-binding reference compound(³H-methyltrienolone) from a soluble cytoplasmic androgen receptorpreparation obtained from cultured LNCap cells (Liao, et al. “The use ofa hydroxylapatite-filter steroid receptor assay method in the study ofthe modulation of androgen receptor interaction.” J. Steroid. Biochem.(1984), 20(1):11-17; with modifications). The procedure involvesincubating cytoplasmic androgen receptor with ³H-methyltrienolone at aconcentration of 0.5 nM. Compounds that interact with the androgenreceptor displace the radioactive reference compound, reducing thenumber of radioactive counts bound to the receptor. Remaining³H-methyltrienolone counts are determined by filtration of the samplethrough a GF/C filter, washing and scintillation counting. Specificligand binding is defined as the difference between the total bindingand non-specific binding determined in the presence of an excess ofunlabeled reference compound. The results are expressed as a percent ofcontrol specific binding. IC₅₀ values (concentration causing ahalf-maximal inhibition of control specific binding) and Hillcoefficients (nH) are determined by non-linear regression analysis ofthe competition curves generated with mean replicate values using theHill equation curve fitting (Y=D+[(A˜D)/(1+(C/C₅₀)^(nH))], whereY=specific binding, D=minimum specific binding, A=maximum specificbinding, C=compound concentration, C₅₀=IC₅₀, and nH=slope factor).Inhibition constants (Ki) are calculated using the Cheng Prusoffequation (Ki=IC₅₀/1+(L/K_(D))), where L=concentration of radioligand inthe assay and K_(D)=affinity of the radioligand for the androgenreceptor. Certain compounds of the invention were tested in this assayand found to be active, greater than 50% inhibition of ligand binding at500 nM of test compound.

Example B2 In Vitro Activity of Compounds of the Invention in AndrogenReceptor Nuclear Translocation Assay (Agonist Format)

The androgen receptor nuclear translocation assay monitors movement ofthe androgen receptor between the cytoplasmic and nuclear compartmentsof PathHunter NHRPro cells (DiscoveRX Corporation, Fremont, Calif.). Inthis assay, an androgen receptor agonist stimulates the translocation ofa ProLabel tagged androgen receptor into the nucleus of PathHunterNHRPro cells where it binds to a complementary nuclear EA fragmentresulting in the formation of an active β-gal enzyme and production of achemiluminescent signal upon treatment of the cells with a β-galsubstrate. Compounds that act as agonists result in an enhancedchemiluminescent signal within these cells.

In the agonist assay format, PathHunter NHRPro cells are incubated inthe presence of varying concentrations of test compound for 5 h at 37°C. After this incubation period, the PathHunter Detection reagentcocktail is added, followed by incubation for 1 h at RT. A luminescentsignal can be read in an appropriate luminometer and reported asrelative luminescent units (RLU).

Example B3 In Vitro Activity of Compounds of the Invention in AndrogenReceptor Nuclear Translocation Assay (Antagonist Format)

Antagonistic properties of compounds are evaluated using the androgenreceptor nuclear translocation assay described above. In the antagonistformat, PathHunter NHRPro cells are treated with varying concentrationsof a reference agonist (trimethylenolone) in order to determine its EC₈₀value (concentration of reference agonist giving rise to 80% maximumsignal). Cells are pretreated with test compound for 1 h at 37° C. priorto the addition of methyltrienolone agonist at a concentration equal toits EC₈₀ value. Treated cells are further incubated at 37° C. for 5 hand signal detection was determined as described for the agonist assay.

Example B4 Phase 1, 2 or 3 Human Clinical Studies

Phase 1-2 or 3 clinical trials may be conducted with a compound asdetailed herein.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

1. A compound of formula (II):

wherein: W¹ is CN, NO₂ or SO₂R⁴; W² is hydrogen, halogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substitutedalkynyl; Z is S, O or NR⁵; Y¹ and Y² are independently hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl,substituted heterocyclyl or Y¹ and Y² are taken together with the carbonto which they are attached to form a cycle which can be heterocyclic,substituted heterocyclic, cycloalkyl or substituted cycloalkyl; Y³ isalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl,heterocyclyl, substituted heterocyclyl carboxyl, formyl, alkyl carbonyl,substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenylcarbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl,substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroarylcarbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynylcarbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substitutedheterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl,N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl,N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substitutedalkoxy carbonyl, halocarbonyl, hydroxymethyl, alkoxymethyl, substitutedalkoxymethyl, thiocarboxyl, thioformyl, alkyl thiocarbonyl, substitutedalkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenylthiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl,aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroarylthiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkylthiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl,heteroaralkyl thiocarbonyl, heterocyclyl thiocarbonyl, substitutedheterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl,N,N-dialkyl thiocarbamyl, N-substituted alkyl thiocarbamyl,N,N-bis-substituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substitutedalkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substitutedalkylthiomethyl; T is carbon or nitrogen and can be at any position inthe ring; R¹ is hydrogen, —C₁-C₈ alkyl-NR^(a)R^(b), —O—C₁-C₈alkyl-NR^(c)R^(d) or —C(O)NR^(e)R^(f), wherein: R^(a) is a C₁-C₁₂ alkyland R^(b) is H or a C₁-C₁₂ alkyl or R^(a) and R^(b) are taken togetherwith the N to which they are attached to form a heterocyclic ring; R^(c)is a C₁-C₁₂ alkyl and R^(d) is H or a C₁-C₁₂ alkyl or R^(c) and R^(d)are taken together with the N to which they are attached to form aheterocyclic ring; R^(e) is a C₁-C₁₂ alkyl and R^(f) is H or a C₁-C₁₂alkyl, or R^(e) and R^(f) are taken together with the N to which theyare attached to form a heterocyclic ring; R² is hydrogen, halo, nitro,alkyl or substituted alkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, aryl or substituted aryl; and if R¹ and R² are bothhydrogen, T is nitrogen.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein; (a) R¹ is —C₁-C₈alkyl-NR^(a)R^(b); (b) R¹ is —C₁-C₈ alkyl-NR^(a)R^(b) and R² is halo; or(c) R¹ is —C₁-C₈ alkyl-NR^(a)R^(b), R² is halo, and at least one of(i)-(v) applies: (i) W¹ is CN; (ii) W² is perhaloalkyl; (iii) Z is S;(iv) Y¹ and Y² are both methyl and (v) T is C.
 3. The compound of claim1 or a pharmaceutically acceptable salt thereof, wherein: (a) R¹ is—O—C₁-C₈ alkyl-NR^(c)R^(d); (b) R¹ is —O—C₁-C₈ alkyl-NR^(c)R^(d) and R²is hydrogen; or (c) R¹ is —O—C₁-C₈ alkyl-NR^(c)R^(d), R² is hydrogen,and at least one of (i)-(v) applies: (i) W¹ is CN; (ii) W² isperhaloalkyl; (iii) Z is S; (iv) Y¹ and Y² are both methyl and (v) T isC.
 4. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein: (a) R¹ is —C(O)NR^(e)R^(f); (b) R¹ is —C(O)NR^(e)R^(f)and R² is halo; or (c) R¹ is —C(O)NR^(e)R^(f), R² is halo, and at leastone of (i)-(v) applies: (i) W¹ is CN; (ii) W² is perhaloalkyl orhydrogen; (iii) Z is S; (iv) Y¹ and Y² are both methyl and (v) T is C.5. The compound of claim 4 or a pharmaceutically acceptable saltthereof, wherein R¹ is —C(O)NR^(e)R^(f), R² is halo, and at least one of(i)-(v) applies: (i) W¹ is CN; (ii) W² is perhaloalkyl or hydrogen;(iii) Z is S; (iv) Y¹ and Y² are both methyl and (v) T is C, R^(e) is aC₁-C₁₂ alkyl and R^(f) is C₁-C₁₂ alkyl.
 6. The compound of claim 4 or apharmaceutically acceptable salt thereof, wherein R¹ is—C(O)NR^(e)R^(f), R² is halo, and at least one of (i)-(v) applies: (i)W¹ is CN; (ii) W² is perhaloalkyl or hydrogen; (iii) Z is S; (iv) Y¹ andY² are both methyl and (v) T is C, wherein R^(e) and R^(f) are takentogether with the N to which they are attached to form a heterocyclicring.
 7. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein T is nitrogen.
 8. The compound of claim 7 or apharmaceutically acceptable salt thereof, wherein at least one of(i)-(iv) applies: (i) W¹ is CN; (ii) W² is perhaloalkyl; (iii) Z is S;(iv) R¹ and R² are both hydrogen.
 9. The compound of claim 7 or apharmaceutically acceptable salt thereof, wherein at least one of(i)-(iv) applies: (i) W¹ is CN; (ii) W² is perhaloalkyl; (iii) Z is S;(iv) R¹ is —C(O)NR^(e)R^(f); and (v) R² is hydrogen.
 10. The compound ofclaim 9 or a pharmaceutically acceptable salt thereof, wherein R^(e) andR^(f) are both hydrogen.
 11. The compound of claim 1, wherein Y isselected from the group consisting of thiocarboxyl, carboxyl,aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, formyl,alkyl carbonyl or alkoxy carbonyl.
 12. The compound of claim 1, which is


13. A pharmaceutical composition, comprising a compound of claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 14. The pharmaceutical composition of claim 13,wherein the compound of claim 1 is


15. A method of treating prostate cancer in an individual in needthereof, comprising administering to the individual an effective amountof a compound of claim 1 or a pharmaceutically acceptable salt thereof.16. The method of claim 15, wherein the individual hascastration-resistant prostate cancer.
 17. The method of claim 15,wherein the individual has hormone-sensitive prostate cancer.
 18. Themethod of claim 15, wherein the compound of claim 1 is